We have shown genetic alterations and microRNA dysregulation in hematopoietic and solid tumors, including lung cancer, the major cause of cancer death in the USA. Recently, we explored microRNA expression profiles in lung tumors, normal lung tissues and plasma samples from cases with variable prognosis involved in a completed spiral CT screening trial with extensive follow up. The trial involved 1025 individuals age 50 years or older, who smoked at least a pack of cigarettes a day for 20 years or more. Profiling of plasma samples collected 1-2 years before the onset of disease, at the time of CT detection, and in disease-free smokers enrolled in the screening trial, provided microRNA expression signatures with strong predictive, diagnostic and prognostic potential (Boeri M. et al. microRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer, Proc. Nat. Acad. Sci. USA, 108:3712-3718, March 1, 2011). These signatures were validated in an independent cohort from a second randomized spiral - CT trial. These results indicate a role of microRNAs as molecular predictors of lung cancer development and aggressiveness and have important clinical implications for lung cancer management. We propose to validate these signatures by using NanoString technology and deep sequencing of microRNAs by taking advantage of large cohorts of patients at NYU (Dr. H. Pass) and at the National Cancer Institute of Italy, Milan, (Drs. U. Pastorino and G. Sozzi). In addition, we propose to investigate the dysregulation of larger non-coding RNAs in the tumors, normal tissues and plasma in the same cohorts of patients, since it could provide novel powerful biomarkers for the early detection and prevention of lung cancer.